A new approach for treating systemic lupus erythematosus (SLE) could lie in targeting iron metabolism in immune system cells. Researchers found that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published in the journal Science Immunology.
Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.
“It has been a real challenge to come up with new therapies for lupus,” said Jeffrey Rathmell, PhD, Vanderbilt University professor. “The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”
Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.
When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anaemic.
“It was not clear why the T cells were high in iron, or what that meant,” said Voss.
To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC.
First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.
The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.
“We see a lot of complications coming from that – the mitochondria don’t function properly, and other signalling pathways are altered,” Voss said.
An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.
“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”
In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.
Since the transferrin receptor mediates iron uptake in many cell types, the researchers want to develop transferrin receptor antibodies that bind specifically to T cells, to minimise off-target effects. They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.
Scanning Electron Micrograph image of a human T cell. Credit: NIH/NIAID
Researchers from the University of Queensland have identified a pathway in cells that could be used to reprogram the body’s immune system to fight back against both chronic inflammatory and infectious diseases such as E. Coli.
Reporting their findings in the open-access journal PNAS, Dr Kaustav Das Gupta and Professor Matt Sweet found that a glucose-derived molecule in immune cells can both stop bacteria growing and dampen inflammatory responses.
According to Dr Das Gupta, the discovery is a critical step towards future therapeutics that train immune cells.
“The effects of this molecule called ribulose-5-phosphate on bacteria are striking – it can cooperate with other immune factors to stop disease-causing strains of the E. coli bacteria from growing,” Dr Das Gupta said.
“It also reprograms the immune system to switch off destructive inflammation, which contributes to both life-threatening infectious diseases such as sepsis as well as chronic inflammatory diseases like respiratory diseases, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, heart disease, stroke, diabetes and dementia.”
The research was carried out on a strain of E. coli bacteria, responsible for 80% of urinary tract infections and also a common cause of sepsis. Pre-clinical trials confirmed the role of this pathway in controlling bacterial infections.
Professor Sweet said that human cells were also used to demonstrate that ribulose-5-phosphate reduces the production of molecules that drive chronic inflammatory diseases.
“Host-directed therapies which train our immune systems to fight infections, will become increasingly important as more types of bacteria become resistant to known antibiotics,” Professor Sweet said.
“A bonus is that this strategy also switches off destructive inflammation, which gives it the potential to combat chronic disease.
“By boosting the immune pathway that generates ribulose-5-phosphate, we may be able to give the body the power to fight back against inflammatory and infectious diseases – not one, but two of the major global challenges for human health.”
Many current anti-inflammatory therapies target proteins on the outside of cells but because this pathway occurs inside cells, the researchers devised a new approach to target the pathway using mRNA technology.
Streptococcus pyogenese bound to a human neutrophil.
Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Griffith University researchers have unlocked one of the secrets as to why some forms of Streptococcus Group A (Strep A) are associated with severe invasive infection. The results, published in mBio, suggest that a toxin it secretes not only damages cells but helps Strep A resist host defence.
Around the world, invasive Strep A diseases are responsible for more than 163 000 deaths annually and a recent increase in cases of invasive Strep A disease has been observed internationally.
For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body.
“The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally,” Associate Professor Pandey said.
“The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study.
“SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection.”
Professor Good said: “We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence.”
“Essentially, the less SLO present, the less severe the case of Strep A.”
SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent.
This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis.
This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.
Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University’s Institute for Glycomics and which is now in a clinical trial.
The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.
In a new entry to the growing list of lasting complications from COVID infection, a large German cohort study of over 600 000 COVIDpatients indicates that new autoimmune conditions may result from previous COVID infection. The findings, which are awaiting peer review on the MedRxiv preprint server, show that the odds of new autoimmune conditions appear to increase in line with the severity of COVID infection.
After the acute phase of infection, some people may develop long-lasting symptoms, known as post-COVID, which are consistent with COVID infection and last more than 12 weeks. Most studies to date have focused on symptoms that partly wane over time. Many studies examined a small selective sample of patients, and only a few studies included a control group or information on chronic health conditions, such as SARS-CoV-2 infection.
Compared to post-COVID emergence of cardiovascular and other diseases, autoimmune diseases are less discussed in the literature, although autoantibodies could be found in patients after SARS-CoV-2 infection. So far there is limited evidence on newly manifested autoimmune diseases after an infection based on several case reports and one recent cohort study using UK health record data. In addition, COVID itself has some similarities with systemic autoimmune rheumatic diseases, which could make diagnosis difficult.
The researchers selected a cohort from German routine health care data, identifying individuals with polymerase chain reaction (PCR)-confirmed COVID through December 31, 2020. Patients were matched 1:3 to control patients without COVID. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyse the onset of autoimmune diseases during the post-acute period. The researchers calculated the incidence rates (IR) per 1000 person-years for each outcome and patient group, and estimated incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding COVID.
In total, 641 704 patients with COVID were included. When comparing the incidence rates in the COVID and matched control groups, the researchers found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID were at a greater risk for incident autoimmune diseases. These risk increases were as follows:
41% higher risk of Grave’s disease
42–45% higher risk of rheumatoid arthritis
25% higher risk of type 1 diabetes
27-29% higher risk of Crohn’s disease
The researchers concluded that SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.
Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.
In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.
Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.
“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.
In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.
In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.
“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”
Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”
In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.
Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.
Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.
A new study suggests that some patients diagnosed with behavioural-variant frontotemporal dementia (bvFTD) – a presently incurable, mentally debilitating condition – may instead have a cerebrospinal fluid leak, which is detectable on MRI scans and often treatable. The researchers say these findings, published in the peer-reviewed journal Alzheimer’s & Dementia: Translational Research and Clinical Interventions, could lead to a cure.
“Many of these patients experience cognitive, behavioural and personality changes so severe that they are arrested or placed in nursing homes,” said Wouter Schievink, MD, professor of Neurosurgery at Cedars-Sinai. “If they have behavioural-variant frontotemporal dementia with an unknown cause, then no treatment is available. But our study shows that patients with cerebrospinal fluid leaks can be cured if we can find the source of the leak.”
When cerebrospinal fluid (CSF) leaks into the body, the brain can sag, causing dementia symptoms. Schievink said many patients with brain sagging, detectable in MRI, go undiagnosed, and he advises clinicians to take a second look at patients with telltale symptoms.
“A knowledgeable radiologist, neurosurgeon or neurologist should check the patient’s MRI again to make sure there is no evidence for brain sagging,” Schievink said.
Clinicians can also ask about a history of severe headaches that improve when the patient lies down, significant sleepiness even after adequate night-time sleep, and whether the patient has ever been diagnosed with a Chiari brain malformation, a condition in which brain tissue extends into the spinal canal. Brain sagging, Schievink said, is often mistaken for a Chiari malformation.
Even when brain sagging is detected, the source of a CSF leak can be difficult to locate. When the fluid leaks through a tear or cyst in the surrounding membrane, it is visible on CT myelogram imaging with the aid of contrast medium.
Schievink and his team recently discovered an additional cause of CSF leak: the CSF-venous fistula. In these cases, the fluid leaks into a vein, making it difficult to see on a routine CT myelogram. To detect these leaks, technicians must use a specialized CT scan and observe the contrast medium in motion as it flows through the cerebrospinal fluid.
In this study, investigators used this imaging technique on 21 patients with brain sagging and symptoms of bvFTD, and they discovered CSF-venous fistulas in nine of those patients. All nine patients had their fistulas surgically closed, and their brain sagging and accompanying symptoms were completely reversed.
“This is a rapidly evolving field of study, and advances in imaging technology have greatly improved our ability to detect sources of CSF leak, especially CSF-venous fistula,” said Keith L. Black, MD, chair of the department of Neurosurgery at Cedars-Sinai. “This specialised imaging is not widely available, and this study suggests the need for further research to improve detection and cure rates for patients.”
The remaining 12 study participants, whose leaks could not be identified, were treated with nontargeted therapies designed to relieve brain sagging, such as implantable systems for infusing the patient with CSF. However, only three of these patients experienced relief from their symptoms.
“Great efforts need to be made to improve the detection rate of CSF leak in these patients,” Schievink said. “We have developed nontargeted treatments for patients where no leak can be detected, but as our study shows, these treatments are much less effective than targeted, surgical correction of the leak.”
The chemical DEET has proven effective at keeping disease-carrying mosquitoes at bay, but the repellent is smelly and its protection is short-lived. Now, researchers report in the Journal of Agricultural and Food Chemistry that they have designed safe alternatives with some advantages over DEET, including a nice smell and much longer protection.
DEET disrupts a mosquito’s ability to locate humans. Until recently, it was considered the gold standard among topical repellents, but some find its strong odor offensive. It has to be reapplied frequently, and at high concentrations, it can damage synthetic fabrics and plastics. Another popular repellent known as picaridin is now regarded as a better alternative, since its protective effect lasts longer, and it doesn’t have an odor or damage items. However, like DEET, it has to be reapplied after swimming or sweating.
So, Francesca Dani and colleagues wanted to look for alternatives to these established products. In prior work, the team used as starting materials two plant-based natural repellents that offered only short-term protection from mosquitoes. The researchers converted these terpenoids into cyclic acetals and hydroxyacetals, thereby extending their protective timespan beyond that of DEET. But the researchers wanted to improve on these initial products.
In the current work, the team synthesised additional cyclic hydroxyacetals from inexpensive, commercially available carbonyls. The new cyclic compounds had pleasant, much fainter odors and were easier to dissolve in water, meaning they can be formulated without high concentrations of alcohol. Some were as effective as DEET and picaridin at repelling Asian tiger mosquitoes, which have spread widely in the U.S. and carry diseases, including encephalitis, dengue and dog heartworm. And like picaridin, they provided human volunteers more than 95% protection from bites for at least eight hours, while DEET’s protection rapidly declined below that level after just two hours.
Toxicity of some of the most active new compounds was comparable to or lower than the traditional repellents. Two hydroxyacetals were also less likely to cause immune reactions or to penetrate cell layers than picaridin. The researchers conclude that their compounds represent a new class of promising mosquito repellents that can compete favorably with DEET and picaridin in terms of efficacy and safety.
In October last year, the National Institute for Communicable Diseases (NICD) alerted the public to a measles outbreak in Limpopo. Since then, four more provinces have reported outbreaks, and the number of positive cases in the country has climbed rapidly.
Last week’s measles report from the NICD indicated that between the first week of October 2022 and mid-week in the second week of January 2023, a total of 397 cases of measles were identified across the country. Of those, 382 cases were detected in five provinces – Limpopo 145, North West 125, Mpumalanga 79, Gauteng 18, and the Free State 15. These five provinces have all met the criteria for a measles outbreak (three or more cases in a district within a month).
The remaining 15 cases are spread around KwaZulu-Natal, Northern Cape, the Eastern Cape, and the Western Cape – none of which have so far met the criteria for an outbreak.
‘Biggest outbreak in 11 years’
Dr Kerrigan McCarthy, a pathologist from the Centre for Vaccines and Immunology at the NICD, tells Spotlight that this is the biggest outbreak in 11 years, surpassing the outbreak in 2017 when around 280 cases of measles were identified.
According to the NICD report, the total number of laboratory-confirmed measles cases and the total number of samples submitted for testing has decreased for the third consecutive week. However, McCarthy cautions that this apparent decline might actually be due to a decrease in the number of specimens sent to the NICD for testing, and not to the outbreak actually slowing down.
“The fact that we have seen a decrease in the number of positive cases could be attributed to the decrease in number of specimens that have been submitted, but there is a small possibility that it could represent a turnaround in the outbreak. However, a consensus amongst us in public health is that it is the former problem,” says McCarthy.
She adds that the true extent of this outbreak – and whether new cases have really declined or not – may only become clear in the next few weeks, as schools across the country resume activities.
While it isn’t possible to predict exactly where the outbreak is going, McCarthy says at the moment it is following a similar trend to the widespread measles outbreak that occurred just over a decade ago. “In 2009 to 2011 we had an outbreak of over 22 000 measles cases… and in fact, in that outbreak, we saw a similar pattern. The outbreak was declared in late 2009 and cases started increasing into December and then when the schools closed and December holidays happened, there was a lull in cases and then when the schools returned there was a massive increase in cases,” she says.
Fears of much larger outbreaks
In a Spotlight article published in July last year, Dr Haroon Saloojee, Professor and Head of the Division of Community Paediatrics at the University of the Witwatersrand, and other experts warned that low vaccination rates may lead to measles outbreaks of the type we are now seeing. Now they are concerned that things might get worse.
Saloojee agrees that it isn’t possible to predict exactly how this outbreak will behave. “There are obviously three possible outcomes,” he says, “An increase, levelling off, or decline. My fear and expectation [are] that the outbreak will continue to expand. There are more than a million unvaccinated children under five, and possibly about 2.5 million unvaccinated under 15 years.
“We should be greatly concerned. It is highly likely that the outbreak will extend beyond the five provinces and affect all provinces in the country,” he says.
He adds that children are protected from measles through vaccination and if 95% of children are vaccinated against measles, then this herd immunity will protect the 5% who are not vaccinated. But in South Africa, measles coverage is not at 95%.
“In South Africa, at best, about 80% of children are vaccinated [against measles]. The proportion is lower in some provinces. Thus, all children, but particularly unvaccinated children, are at risk of acquiring measles,” he says. “We haven’t had a serious problem [with] measles in South Africa for at least the last 20 years. But in other low- and middle-income countries, it is still one of the five major causes of child mortality.”
Mass measles immunisation campaign needed
Saloojee tells Spotlight the only way to curtail the outbreak at this point is through a national supplementary mass measles immunisation campaign.
“There is only one option at this stage, as we are facing a crisis. A national supplementary immunisation campaign is warranted, despite its high cost and resource demands,” he says. “Such activities have already commenced in the affected provinces and will be extended to other provinces if the outbreak continues to spread. The aim of the campaign is to boost measles vaccine coverage to the 95% mark in the short term, so that herd immunity can kick in.”
How did we get here?
While such an immunisation campaign should help mitigate the current spread of measles, the question remains how a widespread outbreak could occur in the first place given South Africa’s well-established childhood immunisation programme.
“The outbreak was entirely predictable and preventable,” says Saloojee. “We have had similar outbreaks [about] every five years since 2000. Paradoxically, COVID delayed this outbreak, which should have happened in 2020 because the isolation measures protected against measles spread too.”
“However, we cannot run away from the fact that too few children receive all their routine vaccinations, and there is little being done to systematically change this such as stopping vaccine stockouts, and clinics and hospitals reducing missed opportunities to vaccinate eligible children,” he says. “If nothing is done, we can count on another outbreak in 2028.”
Countries across the world are reporting measles outbreaks, according to the CDC, which is being attributed to a disruption in services like routine immunisation because of the COVID pandemic. However, according to Saloojee, South Africa’s outbreak cannot be attributed exclusively to the pandemic disrupting services, instead, it is also due to years of suboptimal measles vaccine coverage.
Spotlight previously reported in-depth on results from the 2019 Expanded Programme on Immunisation (EPI) National Coverage survey, which showed that only around 77% (76.8%) of the children surveyed had received all fourteen age-appropriate vaccines from birth to 18 months. This includes the two doses of the measles vaccine.
Dr Lesley Bamford, a child health specialist in youth and school health at the National Department of Health, provided Spotlight with a table showing measles vaccination coverage per province between 2017 and 2022.
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
According to the figures provided by Bamford, national coverage for the first dose of the measles vaccine has improved from 80% in 2017-2018 to 88% in 2021-2022. However, coverage for the second measles dose remained stuck in a narrow band from 77% to 80%, until 2021-2022, when it improved to 84% – still well below the 95% coverage required for herd immunity.
Expanded vaccination campaign
The NICD report shows the highest number of measles cases so far have been in the five to nine-year age group, which represents 40% of cases. 29% of cases were in the one to four age group and 17% in the 10 to 14-year age group. The remaining cases occurred in children younger than one year and those aged 15 and older.
According to McCarthy, based on the distribution of cases in these age groups, the NICD recommended to the National Department of Health that it extend its planned mass measles vaccination campaign to include children between six months and 15 years of age – which the Department has agreed to do.
Bamford tells Spotlight that a mass measles immunisation campaign had already been planned across all provinces for February 2023. But for the five provinces experiencing outbreaks, the timeline has since moved up. The four remaining provinces will still start their campaigns in February as planned.
“The target age group for that campaign has been extended. So, the initial plan was targeting children under 5 years of age and now in most provinces, it has been extended to include all children six months to 15 years of age,” she says.
Spokesperson for the National Department of Health, Foster Mohale confirms that all children between the ages of six months and 15 years, regardless of documentation, are eligible to receive their measles vaccination in the catch-up drive. “Most provinces have been vaccinating all children between 6 months and 15 years, with [or] without documents because diseases have no discrimination. So, we haven’t received any concern or report about non-vaccination of children without documentation,” he says.
Bamford adds that a measles incident management team has been established by the National Department of Health, which meets with the NICD and the provinces on a weekly basis.
She says Limpopo started its campaign in November, Mpumalanga and North West started in December, and Gauteng and the Free State started in January. The campaigns have so far been conducted mainly at primary healthcare clinics and outreach to ECD centres but now that the school year has resumed, children will also be vaccinated at schools.
Because the provinces all started at different times, there is no specific timeline for the vaccination campaign to be completed, according to Bamford, but the expectation from the National Department is that all provinces will wrap up their campaigns by mid-February when the HPV vaccination campaign kicks off.
“We know that measles coverage is suboptimal, and that is why we were planning to run a campaign, but of course, that is the single biggest reason why we are now experiencing these outbreaks,” she says. “The only way really to stop measles outbreaks is to improve immunisation coverage.”
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr
Using a modified version of the bacterium Mycoplasma pneumoniae, researchers have designed the first ‘living medicine’ to treat lung infections. Their method is reported in the journal Nature Biotechnology. The treatment targets Pseudomonas aeruginosa, a common source of hospital-acquired infections and which is naturally multi-drug resistant.
Researchers removed the M. pneumoniae‘s ability to cause disease and repurposing it to attack P. aeruginosa instead. The modified bacterium is used in combination with low doses of antibiotics that would otherwise not work on their own.
Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The ‘living medicine’ doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.
P. aeruginosa infections are difficult to treat because the bacteria lives in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.
P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition affecting 9–27% of patients who require intubation. The incidence exceeds 50% for patients intubated because of severe COVID. VAP can extend the duration in intensive care unit for up to 13 days and kills 9–13% of patients.
The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth of Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.
“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr María Lluch, co-corresponding author of the study.
With the aim of using the ‘living medicine’ to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebuliser.
M. pneumoniae is one of the smallest known species of bacteria. Dr Luis Serrano first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.
One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.
By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers creating new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads – whether these are cytokines, nanobodies or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.
In addition to designing the ‘living medicine’, Dr. Serrano’s research team are also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team are using these proteins to target inflammation caused by P. aeruginosa infections.
Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which release mediator proteins such as cytokines. One type of cytokine, IL-10, has well-known anti-inflammatory properties and is of growing therapeutic interest.
Dr Serrano’s research group used protein-design software to engineer new versions of IL-10 purposefully optimised to treat inflammation. The cytokines were designed to be created more efficiently and to have higher affinity, meaning less cytokines are needed to have the same effect.
The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild type IL-10 cytokine.
According to Dr Ariadna Montero Blay, co-corresponding author of that study, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”
Medical science has not yet been able to explain why the Epstein-Barr virus triggers infectious mononucleosis (IM) in some people with initial infections and not in others. But now researchers have identified a unusual T cell response to the virus as the cause, and as a potential target for the development of vaccines. The findings were recently published in the journal Blood.
T cells normally fight the proliferation of the Epstein-Barr virus (EBV) in humans as part of an antiviral immune response. In this response, certain EBV components (peptides) are presented to the T cells by a specific molecule (HLA-E), which is found on the surface of cells infected with EBV. This triggers a non-classical T-cell response that leads to the destruction of the infected cells. Due to a genetic variation (HLA-E*0103/0103), about one third of the population naturally has more HLA-E molecules on EBV-infected cells.
A recently published study has shown that the risk of developing IM following first-time infection with the Epstein-Barr virus depends strongly on this EBV-specific immune response.
“Our research revealed that people with the HLA-E*0103/0103 genetic variation have a lower risk of developing infectious mononucleosis than those who do not have the variation. Our experiments in the lab showed that this gene variation is associated with a highly pronounced EBV-specific -non-classical — immune response,” explained Hannes Vietzen from MedUni Vienna’s Center for Virology, the first author of the study.
Preventive and diagnostic possibilities
EBV is one of the most common viral infections in humans. On initial infection, the virus causes IM in some children and young adults; this disease is characterised by non-specific symptoms, such as fever, as well as exhaustion that in some cases can last for several months. Until now, it was unclear why a first-time EBV infection only leads to IM in a minority of people, while most do not present any symptoms whatsoever. The immune response that the researchers identified could also be a target for research into preventive measures: “This immune response was still measurable years after the initial EBV infection and generally provides long-lasting protection against reinfection with Epstein-Barr, so it might be worth focusing our attention on this mechanism with a view to developing new vaccines in future,” said Hannes Vietzen, looking ahead.
Another finding from the study could also open up new diagnostic options: “The combination of the unfavourable HLA-E genetic variation with certain EBV peptides also appears to play an important role in the development of EBV-associated lymphomas in transplant recipients,” Hannes Vietzen commented. “Analysis of the EBV strains found in these patients could be helpful in identifying high-risk patients at an early stage and treating them in good time.”
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
